5F5L

The structure of monooxygenase KstA11 in the biosynthetic pathway of kosinostatin

5F5L の概要

• エントリーDOI: 10.2210/pdb5f5l/pdb
• 関連するPDBエントリー: 5F5N
• 分子名称: Monooxygenase, GLYCEROL, 2,3-DIHYDROXY-1,4-DITHIOBUTANE, ... (4 entities in total)
• 機能のキーワード: monooxygenase, dearomatization, kosinostatin, oxidoreductase
• 由来する生物種: Micromonospora sp. TP-A0468
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 31638.95

構造登録者

Pan, L.,Gong, Y. (登録日: 2015-12-04, 公開日: 2016-12-21, 最終更新日: 2024-10-23)

主引用文献

Zhang, Z.,Gong, Y.-K.,Zhou, Q.,Hu, Y.,Ma, H.-M.,Chen, Y.-S.,Igarashi, Y.,Pan, L.,Tang, G.-L.
Hydroxyl regioisomerization of anthracycline catalyzed by a four-enzyme cascade
Proc. Natl. Acad. Sci. U.S.A., 114:1554-1559, 2017

PubMed Abstract: Ranking among the most effective anticancer drugs, anthracyclines represent an important family of aromatic polyketides generated by type II polyketide synthases (PKSs). After formation of polyketide cores, the post-PKS tailoring modifications endow the scaffold with various structural diversities and biological activities. Here we demonstrate an unprecedented four-enzyme-participated hydroxyl regioisomerization process involved in the biosynthesis of kosinostatin. First, KstA15 and KstA16 function together to catalyze a cryptic hydroxylation of the 4-hydroxyl-anthraquinone core, yielding a 1,4-dihydroxyl product, which undergoes a chemically challenging asymmetric reduction-dearomatization subsequently acted by KstA11; then, KstA10 catalyzes a region-specific reduction concomitant with dehydration to afford the 1-hydroxyl anthraquinone. Remarkably, the shunt product identifications of both hydroxylation and reduction-dehydration reactions, the crystal structure of KstA11 with bound substrate and cofactor, and isotope incorporation experiments reveal mechanistic insights into the redox dearomatization and rearomatization steps. These findings provide a distinguished tailoring paradigm for type II PKS engineering.

PubMed: 28137838
DOI: 10.1073/pnas.1610097114

実験手法

X-RAY DIFFRACTION (1.68 Å)